AUTHOR=Kim Ji-Eun , Hyun Hye-Won , Min Su-Ji , Lee Duk-Shin , Jeon A Ran , Kim Min Ju , Kang Tae-Cheon 

TITLE=PLPP/CIN Regulates Seizure Activity by the Differential Modulation of Calsenilin Binding to GluN1 and Kv4.2 in Mice

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=10

YEAR=2017

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2017.00303

DOI=10.3389/fnmol.2017.00303

ISSN=1662-5099

ABSTRACT=<p>Calsenilin (CSEN) binds to Kv4.2 (an A-type K<sup>+</sup> channel) as well as <italic>N</italic>-methyl-<sc>D</sc>-aspartate receptor (NMDAR), and modulates their activities. However, the regulatory mechanisms for CSEN-binding to Kv4.2 or NMDAR remain elusive. Here, we demonstrate the novel role of pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN), one of the cofilin-mediated F-actin regulators, in the CSEN binding to Kv4.2 or GluN1 (an NMDAR subunit). PLPP/CIN dephosphorylated CSEN in competition with casein kinase 1, independent of cofilin dephosphorylation. As compared to wild-type mice, PLPP/CIN transgenic (PLPP/CIN<sup>Tg</sup>) mice showed the enhancement of Kv4.2–CSEN binding, but the reduction in CSEN–GluN1 binding. In addition, PLPP/CIN<sup>Tg</sup> mice exhibited the higher intensity (severity), duration and progression of seizures, but the longer latency of seizure on-set in response to kainic acid. PLPP/CIN knockout mice reversed these phenomena. Therefore, we suggest that PLPP/CIN-mediated CSEN dephosphorylation may play an important role in the functional coupling of NMDAR and Kv4.2, which regulates the neuronal excitability.</p>